| First Author | Idris-Khodja N | Year | 2017 |
| Journal | J Hypertens | Volume | 35 |
| Issue | 7 | Pages | 1390-1401 |
| PubMed ID | 28234672 | Mgi Jnum | J:280031 |
| Mgi Id | MGI:6367539 | Doi | 10.1097/HJH.0000000000001324 |
| Citation | Idris-Khodja N, et al. (2017) Vascular smooth muscle cell peroxisome proliferator-activated receptor gamma protects against endothelin-1-induced oxidative stress and inflammation. J Hypertens 35(7):1390-1401 |
| abstractText | AIMS: Peroxisome proliferator-activated receptor gamma (PPARgamma) agonists reduce blood pressure and vascular injury in hypertensive rodents. Ppargamma inactivation in vascular smooth muscle cells (VSMC) enhances vascular injury. Transgenic mice overexpressing endothelin (ET)-1 selectively in the endothelium (eET-1) exhibit endothelial dysfunction, increased oxidative stress and inflammation. We hypothesized that inactivation of the Ppargamma gene in VSMC (smPpargamma-/-) would exaggerate ET-1-induced vascular injury. METHODS AND RESULTS: eET-1, smPpargamma-/- and eET-1/smPpargamma-/- mice were treated with tamoxifen for 5 days and studied 4 weeks later. SBP was higher in eET-1 and unaffected by smPpargamma inactivation. Mesenteric artery vasodilatory responses to acetylcholine were impaired only in smPpargamma-/-. N(omega)-Nitro-L-arginine methyl ester abrogated relaxation responses, and the Ednra/Ednrb mRNA ratio was decreased in eET-1/smPpargamma-/-, which could indicate that nitric oxide production was enhanced by ET-1 stimulation of endothelin type B receptors. Mesenteric artery media/lumen was greater only in eET-1/smPpargamma-/-. Mesenteric artery reactive oxygen species increased in smPpargamma and were further enhanced in eET-1/smPpargamma-/-. Perivascular fat monocyte/macrophage infiltration was higher in eET-1 and smPpargamma and increased further in eET-1/smPpargamma-/-. Spleen CD11b+ cells were increased in smPpargamma-/- and further enhanced in eET-1/smPpargamma-/-, whereas Ly-6C(hi) monocytes increased in eET-1 and smPpargamma-/- but not in eET-1/smPpargamma-/-. Spleen T regulatory lymphocytes increased in smPpargamma and decreased in eET-1, and decreased further in eET-1/smPpargamma-/-. CONCLUSION: VSMC Ppargamma inactivation exaggerates ET-1-induced vascular injury, supporting a protective role for PPARgamma in hypertension through modulation of pro-oxidant and proinflammatory pathways. Paradoxically, ET-1 overexpression preserved endothelial function in smPpargamma-/- mice, presumably by enhancing nitric oxide through stimulation of endothelin type B receptors. |
